Powder formulations are the mainstay of drug delivery. Pharmaceutical powders are normally formulated as suspensions, dry powders, tablets, powders for reconstitution and capsules. Pharmaceutical powders are used to facilitate drug delivery because of their ease of use and increase in stability of the active ingredient. However, in the last few years, strict control measures by the FDA and other agencies as to dose uniformity, stability and the prohibition of use of commonly used excipients have threatened certain powder products that are currently on the market. Consequently, this has resulted in greater difficulties in compounding successful powder formulations.
Optimization and control of flow and dispersion characteristics of a powder formulation are of critical importance in the development of powder products and, in particular, powder inhalation products. These characteristics are a function of the principal adhesive forces between particles such as van der waals forces, electrostatic forces and the respective surface tensions of absorbed liquid layers. These forces are influenced by several fundamental physicochemical properties including particle density and size distribution, particle morphology (shape, habit, surface roughness) and surface composition (including absorbed moisture). Interparticle forces that influence flow and dispersion properties are particularly dominant in the micronized or microcrystalline powders that are required for inhalation. Attempts to overcome these forces such as blending a drug with a carrier and adding excipients have been made but have met with limited success. For example, blending a drug with a carrier provides some advantages such as increasing the bulk of the formulation which allows for easier metering of small quantities of potent drugs either at the manufacturing stage or within a delivery device such as a reservoir type device. However, significant disadvantages are evident such as drug/excipient segregation, which severely impacts the dosing and the shelf-life of the composition.
Another approach in drug delivery that has been investigated widely is the incorporation of a drug with excipients by freeze-drying or spray drying. Spray drying is commonly used in the pharmaceutical industry for various substances such as antibiotics, vitamins, vaccines, enzymes, plasma and other excipients as well as for preparation of microcapsules and slow release formulations. Spray drying has gained interest due to the technique's simplicity, low cost, versatility and overall effectiveness. Spray drying is sometimes regarded as a harsh method when compared to freeze-drying due to the high temperature of the drying gas which can be detrimental to sensitive biological materials. However, when considering the spray drying process in greater detail, it is evident that the spray droplets and the dried powder particles maintain a temperature well below the inlet temperature of the drying gas throughout the entire process. As long as water is evaporated from the droplets, a cooling effect is achieved thereby preventing exposure of the product to high temperatures.
Millqvist-Fureby (Int. J. Pharm., 1999, 188, 243-253) has shown the advantages of spray drying trypsin versus freeze-drying where it was demonstrated that the activity loss of trypsin was reduced when it was spray dried instead of freeze-dried. This was explained by the “vitrification” hypothesis which states that it is essential to maintain an excipient in an amorphous or “glassy” state to prevent the protein from changing its shape due to the rigidity of the matrix (Franks, 1991, Biopharma 4, 38-55). These findings, particularly regarding the effect of carbohydrates (most of which tend to crystallize when frozen) and the fact that surface active components experience physical changes in the drying process, which in the case of certain compounds (proteins) are detrimental to functionality of that compound (i.e. activity loss of the protein), show the advantages of spray drying.
Those skilled in the art know that powders have a tendency to be amorphous by nature and that amorphous structures are not stable. Amorphous forms of many drugs and excipients can be produced during processing and revert to the thermodynamically stable crystalline form on storage. The amorphous form will have different physical properties and as such will interact with other phases (i.e. other formulation components, whether these are powders or liquids) in a different manner than that of the crystalline form. An additional complication in systems that contain amorphous material is that the amorphous structure can change under varying conditions and may collapse when exposed to humid air. It has also been known for many years that amorphous materials can collapse when above their glass transition temperature due to the inability of the rubbery material to support its own weight under gravity. For example, lactose is a commonly used excipient which in its amorphous state (micronization, spray drying, freeze-drying, etc.) exhibits varying degrees of structural collapse when held at 50% relative humidity (“RH”). Buckton (1995 Int. J. Pharm. 123, 265-271) noted that water was rapidly absorbed and desorbed by a structure prior to collapse but water sorption to and from the collapsed structure was slow and controlled by diffusion in the solid, rather than just by external relative humidity.
The presence of water in amorphous materials is of importance for two principal reasons. The first reason is called the amplification process (Ahlneck, 1990 Int. J. Pharm., 62, 87-95) which states that a sample containing 0.5% amorphous material and 0.5% associated water will in reality have most of the water absorbed in the amorphous region. If this amorphous excipient material is responsible for maintaining the integrity and the structure of the particle, the physical and chemical stability of the product will be in jeopardy. The second reason water is important is the retention of water in amorphous regions of the sample. Water that is absorbed in a non-collapsed amorphous structure will desorb rapidly and be easily dried; however, if the water is in a collapsed region, this will not hold true and the water will only be able to be removed slowly by diffusion through that region. Once the structure has collapsed, even if the powder is dried, the powder has gone through irreversible transformations that will compromise the integrity of the powder. Thus, water is recognized to be the enemy in the performance and in the physical and chemical stability of most drug formulations including dry powders.
Another important consideration as to the presence of water is the characterization of the effects of sorbed water with glassy drug formulation on the glass transition temperature (“Tg”). The relationship between water content and Tg has been explored in a number of publications in the pharmaceutical literature (e.g., Hancock, 1994 Pharm. Res. 11, 471-477). The presence of water is known to lower the Tg of amorphous systems and it has been well established that the presence of water will plasticize the host material leading to a high probability of physical and chemical instability. Andoris (1998 Pharm. Res. 15, 835-842) and Hancock (1997, J Pharm. Sci. 86, 1-12) have addressed the issue of the relationship between storage temperature and the crystallization of amorphous material. These authors have suggested that as long as amorphous materials are stored at approximately 50° C. below their Tg, the amorphous materials should be both physically and chemically stable since molecular mobility will be reduced.
The extent of the depression of Tg can be related to the weight fraction of sorbed water. The relationship between moisture uptake and Tg may be described in terms of the Gordon-Taylor relationship (Gordon, 1952, J. Appl. Chem. 2, 493-500). Assuming perfect volume additivity with no specific interaction between the components, the glass transition of the mixture, Tgmix, is given by the following formula:Tgmix=φ1Tg1+φ2Tg2  (1)where φ is the volume fraction and the subscripts represent the two components. Re-defining the equation in terms of weight fractions, the formula is:
                              T                      g            mix                          =                                            (                                                w                  1                                ⁢                                  T                                      g                    ⁢                                                                                  ⁢                    1                                                              )                        +                          (                                                Kw                  2                                ⁢                                  T                                      g                    ⁢                                                                                  ⁢                    2                                                              )                                                          w              1                        +                          Kw              2                                                          [        2        ]            where w1 and w2 are the weight fractions of water and drug respectively and K can be considered to be the ratio of the free volumes of the two components. The Tg of water has been published to be 135° K (Sugisaki 1968, Bull. Chem. Soc. Jpn. 41, 2591-2599) with a K value of 0.198.
Even relatively small amounts of water might be detrimental to the stability of amorphous materials which leads to the question of how much water is necessary to lower the Tg to below the storage temperature, thereby considerably increasing the risk of product failure. The amount of water necessary to lower the Tg to below the storage temperature can be estimated by considering the Simha-Boyer rule:
                    K        =                                            ρ              1                        ⁢                          T                              g                ⁢                                                                  ⁢                1                                                                        ρ              2                        ⁢                          T                              g                ⁢                                                                  ⁢                2                                                                        [        3        ]            where ρ1 and ρ2 are the densities of materials one and two respectively and Tg1 and Tg2 are the glass transition temperatures of materials one and two respectively (Simha, J. Chem. Phys. 1962, 37, 1003-1007).
Royall (Int. J. Pharm. 1999, 192, 39-46) derived an equation that estimates the critical moisture content (wc) which would result in the value of Tg falling to a value 50° K above the storage temperature, thereby providing a much greater margin of safety with regard to the possibility of collapsed structures:
                              w          c                =                              [                          1              +                                                                    T                                          g                      ⁢                                                                                          ⁢                      2                                                        ⁢                                                            ρ                      2                                        ⁡                                          [                                                                        T                          ST                                                -                        85                                            ]                                                                                        135                  ⁡                                      [                                                                  T                                                  g                          ⁢                                                                                                          ⁢                          2                                                                    -                                              T                        ST                                            -                      50                                        ]                                                                        ]                                -            1                                              [        4        ]            where TST is the storage temperature and Tg2 is the transition temperature of the dry mixture and ρ1 and ρ2 are the densities of materials one and two respectively.
The use of lipids (e.g., free fatty acids and their salts as well as phospholipids) in powder formulations is well accepted in the pharmaceutical industry due to lipids' biotolerability and their physical and chemical characteristics. Polar head groups and surface area of lipids play a functional role at different molecular levels in the context of metal ion-lipid binding. The surface area per lipid molecule together with its electrical charge determines the membrane surface potential ψo. The electrical charge of the lipid molecule regulates the attraction or repulsion of cations at the lipid-water interface.
The tendency of metal ions to form several coordination bonds with phospholipid head groups can reduce the distance between head groups, thus stretching the hydrocarbon chains into an all-trans conformation. A hydrocarbon chain in the all-trans conformation has a cross-section of approximately 24 Å2, thus yielding a minimum area of about 48 Å2 for a crystalline phospholipid with two hydrocarbon chains. The “crystallization” phenomenon induced by the cation will reduce molecular mobility which is the cause of is instability for certain formulations. In the absence of organization by metal cations, the hydrocarbon chains are disordered, with a direct consequence of lateral expansion of the lipid membrane. In the liquid-crystalline state, the average cross-sectional area for this lipid increases to about 60 Å2 (Büldt, 1979, J. Mol. Biol., 134, 673).
The increase in the chain-melting transition (“crystallization”) temperature may exceed 50° C. if the interfacially bound ions have displaced most of the water from the interface. Essentially, anhydrous lipid-ion complexes in excess solution are no exception. One example of this are multivalent metal-ion complexes of diacylphosphatidylserine bilayers (Hauser, 1981, Biochemistry, 23, 34-41). These bilayers form highly ordered, essentially water free bilayers with extremely high transition temperatures in the range between 151-155° C. However, the highest chain-melting phase transition temperatures for diacylphospholipid membranes with monovalent ions or protons bound to the headgroup do not exceed 100° C. due to the lack of strong intermolecular ionic coupling.
Ion-induced phase transition shifts can move in either direction. When a membrane-ion complex binds water more strongly than the membrane surface without bound ions, the ion-induced shift of the bilayer main transition temperature is downwards. This is the case with phosphatidylcholine in the presence of anions or with phosphatidylserine with bound organic counter ions. The chain-melting phase transition temperature for such systems therefore decreases with the increasing bulk electrolyte concentration.
Phospholipid affinity for cations generally follows the sequence:                Lanthanides>transition metals>alkaline earth metals>alkali metals        
It is an object of the present invention to provide powdered pharmaceutical compositions for drug delivery that exhibit improved stability and dispersability over the shelf life of the compositions. It is a further object of the invention to avoid the usage of excipients that will reduce the shelf-life of the compositions. It is a further object of the invention to incorporate the drug or active ingredient with the particle avoiding active compound segregation. It is a further object of the invention to provide a novel drug delivery system that is capable of maintaining a high level of dispersability over time.